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Among the mechanisms mediating resistance, overexpression of anti\u2010apoptotic Bcl\u20102 proteins (Bcl\u20102, Bcl\u2010x<jats:sub>L<\/jats:sub>, Mcl\u20101) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl\u20102 proteins were analysed in a pan\u2010cancer cohort from the NCT\/DKFZ\/DKTK MASTER registry trial (<jats:italic>n<\/jats:italic>\u00a0=\u00a01140, CCA <jats:italic>n<\/jats:italic>\u00a0=\u00a072) via RNA\u2010sequencing and transcriptome\u2010based protein activity interference revealing high ranks of CCA for Bcl\u2010x<jats:sub>L<\/jats:sub> and Mcl\u20101. Expression of Bcl\u2010x<jats:sub>L<\/jats:sub>, Mcl\u20101, and Bcl\u20102 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative\u2010RT\u2010PCR. Immunohistochemistry confirmed the upregulation of Bcl\u2010x<jats:sub>L<\/jats:sub> and Mcl\u20101 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl\u2010x<jats:sub>L<\/jats:sub> (Wehi\u2010539), of Mcl\u20101 (S63845), and Bcl\u20102 (ABT\u2010199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl\u2010x<jats:sub>L<\/jats:sub> induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl\u2010x<jats:sub>L<\/jats:sub> and Mcl\u20101 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl\u20102 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl\u2010x<jats:sub>L<\/jats:sub> in CCA depending on the CCA subtype. Collectively, these observations identify Bcl\u2010x<jats:sub>L<\/jats:sub> as a key protein in cell death resistance of CCA and may pave the way for clinical application.<\/jats:p>","DOI":"10.1111\/liv.15392","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T11:19:23Z","timestamp":1660907963000},"page":"2855-2870","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<scp>Bcl\u2010x<sub>L<\/sub><\/scp> as prognostic marker and potential therapeutic target in cholangiocarcinoma"],"prefix":"10.1111","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5830-3616","authenticated-orcid":false,"given":"Paula","family":"Hoffmeister\u2010Wittmann","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg University Hospital Heidelberg  Heidelberg Germany"},{"name":"Department of Radiooncology University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Mock","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg University Hospital Heidelberg  Heidelberg Germany"},{"name":"Department of Translational Medical Oncology NCT Heidelberg and German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"German Cancer Consortium (DKTK), Heidelberg and Partner Sites  Heidelberg Germany"},{"name":"Institute of Pathology, Medical Faculty Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Nichetti","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Fondazione IRCCS Istituto Nazionale Dei Tumori  Milan Italy"},{"name":"Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Korell","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK), Heidelberg and Partner Sites  Heidelberg Germany"},{"name":"Department of Medicine V University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph E.","family":"Heilig","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Oncology NCT Heidelberg and German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"German Cancer Consortium (DKTK), Heidelberg and Partner Sites  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna\u2010Lena","family":"Scherr","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"G\u00fcnther","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK), Heidelberg and Partner Sites  Heidelberg Germany"},{"name":"Institute of Pathology, Medical Faculty Ludwig\u2010Maximilians\u2010University  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2234-0909","authenticated-orcid":false,"given":"Thomas","family":"Albrecht","sequence":"additional","affiliation":[{"name":"Institute for Pathology University Hospital Heidelberg  Heidelberg Germany"},{"name":"Liver Cancer Center Heidelberg University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eblina","family":"Kelmendi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg University Hospital Heidelberg  Heidelberg 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Carus Technische Universit\u00e4t Dresden, Dresden, Germany; Helmholtz\u2010Zentrum Dresden \u2010 Rossendorf (HZDR)  Dresden Germany"},{"name":"German Cancer Consortium (DKTK) Dresden  Germany"},{"name":"Translational Functional Cancer Genomics National Center f\u00fcr Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Brors","sequence":"additional","affiliation":[{"name":"Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"H\u00fcllein","sequence":"additional","affiliation":[{"name":"Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ)  Heidelberg 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